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Fulltext Effectiveness of tocotrienol-rich fraction combined with tamoxifen in the management of women with early breast cancer: a pilot clinical trial

Nesaretnam K, Selvaduray KR, Abdul Razak G, Veerasenan SD, Gomez PA

Breast Cancer Res, 2010;12(5):R81.
PMID: 20929592 DOI: 10.1186/bcr2726

Basic research has indicated that tocotrienols have potent antiproliferative and proapoptotic effects that would be expected to reduce the effect of breast cancer.

Study site: Hospital Kuala Lumpur

Matched MeSH terms: Tamoxifen/administration & dosage*
Tamoxifen Suppresses the Growth of Malignant Pleural Mesothelioma Cells

Jennings CJ, Zainal N, Dahlan IM, Kay EW, Harvey BJ, Thomas W

Anticancer Res, 2016 11;36(11):5905-5913.
PMID: 27793915

Malignant pleural mesothelioma (MPM) is a rare but highly aggressive malignancy most often associated with exposure to asbestos. Recent evidence points to oestrogen receptor (ER)-β having a tumour-suppressor role in MPM progression, and this raises the question of whether selective modulators of ERs could play a role in augmenting MPM therapy.

Matched MeSH terms: Tamoxifen/administration & dosage
Review: Patient-controlled transdermal 4-hydroxytamoxifen (4-OHT) vs. oral tamoxifen: A systematic review and meta analysis

Sundralingam U, Khan TM, Elendran S, Muniyandy S, Palanisamy UD

Pak J Pharm Sci, 2019 May;32(3):1121-1128.
PMID: 31278729

There has been a number of studies looking into an alternative mode of therapy for the treament of breast cancer via 4-hydroxytamoxifen (4-OHT) transdermal administration.This systematic review aims to compare the safety and efficacy of a transdermal 4-OHT local therapy and oral tamoxifen (oral-T) on the treatment of ductal carcinoma in situ breast cancer. Through a systematic search of health science databases, eligible trials were located and the end points assessed were Ki-67 labeling index, concentration of 4-OHT in breast adipose tissue (ng/g) and plasma (ng/ml). Revman 5.3 version was used to perfom the meta-analysis. Three trials were identified (n=103), while only two were included for meta analysis. The mean difference between the two studies included were 0.40 and -10.58. Overall the I2 value was 89.0%, (Tau2 =53.86) and the differences between the two trials were statistically significant p=0.002. The meta analysis of the randomized controlled trials showed that the use of local transdermal therapy of 4-OHT gel is more safer than oral-T. However, due to the limited number of studies, the potential use of 4-OHT topical transdermal therapy for the treatment of breast cancer could not be concluded for healthcare professionals.

Matched MeSH terms: Tamoxifen/administration & dosage*
Fulltext Synergistic anticancer effects of a bioactive subfraction of Strobilanthes crispus and tamoxifen on MCF-7 and MDA-MB-231 human breast cancer cell lines

Yaacob NS, Kamal NN, Norazmi MN

BMC Complement Altern Med, 2014;14:252.
PMID: 25034326 DOI: 10.1186/1472-6882-14-252

Development of tumour resistance to chemotherapeutic drugs and concerns over their toxic effects has led to the increased use of medicinal herbs or natural products by cancer patients. Strobilanthes crispus is a traditional remedy for many ailments including cancer. Its purported anticancer effects have led to the commercialization of the plant leaves as medicinal herbal tea, although the scientific basis for its use has not been established. We previously reported that a bioactive subfraction of Strobilanthes crispus leaves (SCS) exhibit potent cytotoxic activity against human breast cancer cell lines. The current study investigates the effect of this subfraction on cell death activities induced by the antiestrogen drug, tamoxifen, in estrogen receptor-responsive and nonresponsive breast cancer cells.

Matched MeSH terms: Tamoxifen/administration & dosage
Dosage-dependent reduction of macular pigment optical density in female breast cancer patients receiving tamoxifen adjuvant therapy

Lim IL, Loo AVP, Subrayan V, Khang TF, See MH, Alip A, et al.

Breast, 2018 Jun;39:117-122.
PMID: 29660599 DOI: 10.1016/j.breast.2018.04.003

It is now increasingly common for breast cancer patients to receive adjuvant tamoxifen therapy for a period of up to 10 years. As survival rate increases, managing tamoxifen ocular toxicities is important for patients' quality of life. Macular pigments in photoreceptor cells protect against free radical damage, which can cause macular degeneration. By reducing macular pigment concentration, tamoxifen may increase the risk of macular degeneration. Here, we compared macular pigment optical density (MPOD) and central macular thickness between breast cancer patients on tamoxifen adjuvant therapy (n = 70), and a control group (n = 72). Multiple regression analysis indicated that MPOD decreases with increasing tamoxifen dosage, up to a threshold of about 20 g, after which MPOD plateaus out. Mean MPOD in the treatment group (mean = 0.40) was significantly lower (p-value = 0.02) compared to the control group (mean = 0.47) for the left eye, and for the right eye (treatment mean = 0.39; control mean = 0.48; p-value = 0.009). No significant difference in mean central macular thickness was found between the treatment and the control group (p-values > 0.4). In the control group, MPOD and central macular thickness showed significant correlation (r∼0.30; p-values tamoxifen dosage, and highlight the potential of tamoxifen to reduce macular pigment concentration through an unknown mechanism that does not depend on macular thinning solely.

Matched MeSH terms: Tamoxifen/administration & dosage
Tamoxifen-loaded nanostructured lipid carrier as a drug delivery system: characterization, stability assessment and cytotoxicity

How CW, Rasedee A, Manickam S, Rosli R

Colloids Surf B Biointerfaces, 2013 Dec 1;112:393-9.
PMID: 24036474 DOI: 10.1016/j.colsurfb.2013.08.009

Cancer nanotherapeutics is beginning to overwhelm the global research and viewed to be the revolutionary treatment regime in the medical field. This investigation describes the development of a stable nanostructured lipid carrier (NLC) system as carrier for Tamoxifen (TAM). The TAM-loaded NLC (TAM-NLC) developed with 200mg of TAM showed a spherical particle with the size of 46.6nm, polydispersity index of 0.267, entrapment efficiency of 99.74% and with the zeta potential of -23.78mV. Besides, the equivalent cytotoxicity of TAM and TAM-NLC to human (MCF-7) and mice (4T1) mammary breast cancer cell lines were observed. Incubating the formulation at the physiological pH resulted into reduced Ostwald ripening rate but without any significant change in the absorptivity. When coupled with the measurements of zeta potential and Ostwald ripening rate, the absorbance assay may be used to predict the long-term stability of drug-loaded nanoparticle formulations. The results of the study also suggest that TAM-NLC is a promising drug delivery system for breast cancer therapy. This is the first encouraging report on the in vitro effect of TAM-NLC against human and mouse mammary adenocarcinoma cell lines.

Matched MeSH terms: Tamoxifen/administration & dosage*
Treatment options for locally advanced breast cancer--experience in an Asian tertiary hospital

Chong HY, Taib NA, Rampal S, Saad M, Bustam AZ, Yip CH

Asian Pac J Cancer Prev, 2010;11(4):913-7.
PMID: 21133600

BACKGROUND: Locally advanced breast cancer (LABC) is characterized by the presence of a large primary tumour (>5 cm) associated with or without skin or chest-wall involvement (T4) or with fixed (matted) axillary lymph nodes in the absence of any evidence of distant metastases. These cancers are classified as stage IIIA and IIIB according to the AJCC Staging System. Treatment of choice involves combinations of surgery, chemotherapy, radiotherapy and/or hormonal therapy. Current guidelines recommend primary surgery or neoadjuvant therapy followed by surgery. The primary objective of this study was to compare the outcome of LABC patients subjected to neoadjuvant chemotherapy before surgery and those who underwent surgery as the primary treatment and to determine prognostic predictors. Secondary objectives were to evaluate the response after neoadjuvant therapy and to determine the treatment compliance rate.
METHODS: This retrospective study of Stage III breast cancer patients was conducted over a 5 year period from 1998 to 2002. The survival data were obtained from the National Registry of Births and Deaths with the end-point of the study in April 2006. The Kaplan Meier method was applied for survival analysis. Cox regression analysis by stepwise selection was performed to identify important prognostic factors.
RESULTS: Out of a 155 evaluable patients, 74 (47.7%) had primary surgery, 62 (40%) had neoadjuvant chemotherapy, 10 patients (6.5%) were given Tamoxifen as the primary treatment, while 9 patients (5.8%) defaulted any form of treatment. After neoadjuvant chemotherapy, 9 patients defaulted further treatment, leaving 53 evaluable patients. Out of these 53 evaluable patients, 5 patients (9.4%) had complete pathological response, 5 (9.4%) a complete clinical response, and 26 (49.1%) had partial response after neoadjuvant chemotherapy. The 5-year survival in the primary surgery group was 56.7 % compared to 44.7% in the neoadjuvant chemotherapy group (p<0.01). The important prognostic factors were race, size of tumour, nodal status, estrogen receptor status and response to neoadjuvant chemotherapy.
CONCLUSION: Patients who had primary surgery had better survival than those who underwent neoadjuvant chemotherapy, which may be due to bias in the selection of patients for neoadjuvant chemotherapy. Out of a total of 155 patients, 25.1% defaulted part of the treatment, or did not receive optimal treatment, emphasizing the importance of psychosocial support and counselling for this group of patients.

Matched MeSH terms: Tamoxifen/administration & dosage*
Incidence of chemotherapy-induced ovarian failure in premenopausal women undergoing chemotherapy for breast cancer

Tiong V, Rozita AM, Taib NA, Yip CH, Ng CH

World J Surg, 2014 Sep;38(9):2288-96.
PMID: 24700093 DOI: 10.1007/s00268-014-2542-y

Breast cancer is increasingly reported in young premenopausal women in Asia. Adjuvant chemotherapy improves survival; however, it has a unique consequence of ovarian failure in premenopausal patients.

Matched MeSH terms: Tamoxifen/administration & dosage
Tissue-selective expression of a conditionally-active ROCK2-estrogen receptor fusion protein

Samuel MS, Rath N, Masre SF, Boyle ST, Greenhalgh DA, Kochetkova M, et al.

Genesis, 2016 Dec;54(12):636-646.
PMID: 27775859 DOI: 10.1002/dvg.22988

The serine/threonine kinases ROCK1 and ROCK2 are central mediators of actomyosin contractile force generation that act downstream of the RhoA small GTP-binding protein. As a result, they have key roles in regulating cell morphology and proliferation, and have been implicated in numerous pathological conditions and diseases including hypertension and cancer. Here we describe the generation of a gene-targeted mouse line that enables CRE-inducible expression of a conditionally-active fusion between the ROCK2 kinase domain and the hormone-binding domain of a mutated estrogen receptor (ROCK2:ER). This two-stage system of regulation allows for tissue-selective expression of the ROCK2:ER fusion protein, which then requires administration of estrogen analogues such as tamoxifen or 4-hydroxytamoxifen to elicit kinase activity. This conditional gain-of-function system was validated in multiple tissues by crossing with mice expressing CRE recombinase under the transcriptional control of cytokeratin14 (K14), murine mammary tumor virus (MMTV) or cytochrome P450 Cyp1A1 (Ah) promoters, driving appropriate expression in the epidermis, mammary or intestinal epithelia respectively. Given the interest in ROCK signaling in normal physiology and disease, this mouse line will facilitate research into the consequences of ROCK activation that could be used to complement conditional knockout models. Birth Defects Research (Part A) 106:636-646, 2016. © 2016 Wiley Periodicals, Inc.

Matched MeSH terms: Tamoxifen/administration & dosage
ROCK2/ras(Ha) co-operation induces malignant conversion via p53 loss, elevated NF-κB and tenascin C-associated rigidity, but p21 inhibits ROCK2/NF-κB-mediated progression

Masre SF, Rath N, Olson MF, Greenhalgh DA

Oncogene, 2017 May 04;36(18):2529-2542.
PMID: 27991921 DOI: 10.1038/onc.2016.402

To study ROCK2 activation in carcinogenesis, mice expressing 4-hydroxytamoxifen (4HT)-activated ROCK2 (K14.ROCK(er)) were crossed with mice expressing epidermal-activated ras(Ha) (HK1.ras(1205)). At 8 weeks, 4HT-treated K14.ROCK(er)/HK1.ras(1205) cohorts exhibited papillomas similar to HK1.ras(1205) controls; however, K14.ROCK(er)/HK1.ras(1205) histotypes comprised a mixed papilloma/well-differentiated squamous cell carcinoma (wdSCC), exhibiting p53 loss, increased proliferation and novel NF-κB expression. By 12 weeks, K14.ROCK(er)/HK1.ras(1205) wdSCCs exhibited increased NF-κB and novel tenascin C, indicative of elevated rigidity; yet despite continued ROCK2 activities/p-Mypt1 inactivation, progression to SCC required loss of compensatory p21 expression. K14.ROCK(er)/HK1.ras(1205) papillomatogenesis also required a wound promotion stimulus, confirmed by breeding K14.ROCK(er) into promotion-insensitive HK1.ras(1276) mice, suggesting a permissive K14.ROCK(er)/HK1.ras(1205) papilloma context (wound-promoted/NF-κB(+)/p53(-)/p21(+)) preceded K14.ROCK(er)-mediated (p-Mypt1/tenascin C/rigidity) malignant conversion. Malignancy depended on ROCK(er)/p-Mypt1 expression, as cessation of 4HT treatment induced disorganized tissue architecture and p21-associated differentiation in wdSCCs; yet tenascin C retention in connective tissue extracellular matrix suggests the rigidity laid down for conversion persists. Novel papilloma outgrowths appeared expressing intense, basal layer p21 that confined endogenous ROCK2/p-Mypt1/NF-κB to supra-basal layers, and was paralleled by restored basal layer p53. In later SCCs, 4HT cessation became irrelevant as endogenous ROCK2 expression increased, driving progression via p21 loss, elevated NF-κB expression and tenascin C-associated rigidity, with p-Mypt1 inactivation/actinomyosin-mediated contractility to facilitate invasion. However, p21-associated inhibition of early-stage malignant progression and the intense expression in papilloma outgrowths, identifies a novel, significant antagonism between p21 and ras(Ha)/ROCK2/NF-κB signalling in skin carcinogenesis. Collectively, these data show that ROCK2 activation induces malignancy in ras(Ha)-initiated/promoted papillomas in the context of p53 loss and novel NF-κB expression, whereas increased tissue rigidity and cell motility/contractility help mediate tumour progression.

Matched MeSH terms: Tamoxifen/administration & dosage
Fulltext Development of erythropoietin receptor-targeted drug delivery system against breast cancer using tamoxifen-loaded nanostructured lipid carriers

Beh CY, How CW, Foo JB, Foong JN, Selvarajah GT, Rasedee A

Drug Des Devel Ther, 2017;11:771-782.
PMID: 28352153 DOI: 10.2147/DDDT.S123939

Tamoxifen (TAM) has been used in the treatment of breast cancers and is supplemented with erythropoietin (EPO) to alleviate the cancer-related anemia. The purported deleterious effects caused by the use of EPO with chemotherapeutic agents in the treatment of cancer-related anemia vary across studies and remain controversial. The use of nanoparticles as a drug delivery system has the potential to improve the specificity of anticancer drugs. In this study, we simultaneously incorporated two pharmacological active ingredients in one nanocarrier to develop EPO-conjugated TAM-loaded lipid nanoparticles (EPO-TAMNLC), a targeted delivery system, to enhance the cytotoxic activity while reducing the side effects of the ingredients. The effect of temperature in modulating the thermodynamic parameters associated with the binding of EPO and TAMNLC was assessed using isothermal titration calorimetry, while the unfolding of EPO structure was determined using fluorescence-quenching approach. The association efficiency of EPO and TAMNLC was 55.43%. Unlike binding of albumin to TAMNLC, the binding of EPO to TAMNLC occurred through endothermic and entropy-driven reaction. The EPO-TAMNLC formulation was stable because of the hydrophobic interaction and the high free energy, suggesting the spontaneity of the interactions between EPO and TAMNLC. The EPO-TAMNLC enhanced the in vitro cytotoxicity of TAM to MCF-7 cells. The EPO surface-functionalized TAMNLC could sequentially deliver EPO and TAM as well as improving site-specific delivery of these therapeutic compounds.

Matched MeSH terms: Tamoxifen/administration & dosage*